Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective agent in a variety of retinal degeneration animal models. In recent years, CNTF secreted from an encapsulated cell device has been evaluated in several clinical trials, and the FDA has granted this CNTF therapy an Orphan Drug Status for the treatment of retinitis pigmentosa (RP) and dry age-related macular degeneration (AMD). Yet despite the potential of CNTF as a broad-spectrum therapeutic agent for different blinding diseases, its mechanisms of action in the retina remain poorly understood. We have shown previously that constitutive, high-level expression of CNTF prevents photoreceptor death but alters retinal gene expression and suppresses visual function. Recently, we have explored the mechanism of CNTF action using genetic perturbations in an RP mouse model treated with the same human CNTF used in clinical trials. By performing retinal cell type specific gene deletions, we have shown that the initial targets of CNTF are Mller glial cells, and without a functional cytokine receptor in Mler glia, downstream signaling events and CNTF-induced photoreceptor survival are abolished. Although the rod photoreceptors do not directly respond to exogenous CNTF, they also require a functional cytokine receptor for survival. Furthermore, we have provided evidence that exogenous CNTF stimulates and amplifies a signaling loop between Mller glia and photoreceptors to promote neuronal viability. However, despite a significant improvement in photoreceptor morphology and viability, low levels of exogenous CNTF only stabilize but do not further enhance retinal function. The proposed research will combine advanced molecular genetics and system biology approaches to investigate the mechanisms underlying CNTF-induced neuroprotection in the retina. We will determine the functions of specific signaling modalities activated by CNTF in rod photoreceptors and Mller glia by using genetically modified mice. We will analyze CNTF-induced changes at the epigenome and transcriptome levels in rod cells by comparing wild type and mutant retinas to decipher critical cellular processes affecting cell survival and function. We will also evaluate the effect of CNTF treatment on cellular metabolism in diseased retinas and define the signaling effector mediating the effect. The proposed research will advance our understanding of neuroprotection mechanisms, provide insight into the effects of CNTF in human retinas, and facilitate the development of more efficacious treatments for retinal degeneration.